9-Hydroxy-7,8,9,10-tetrahydro-6H, dibenzo[b][d] pyrans and pyranones

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is methyl or R 1  R 1  is oxygen; R 2  is alkyl or halogen substituted phenyl alkyl; and R 3  is hydrogen, loweralkyl, loweralkenyl or loweralkynyl. 
     The compounds of this invention are useful as analgesics and tranquilizers.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to benzopyrans and more particularly to9-hydroxy-7, 8, 9, 10-tetrahydro-6H-dibenzo [b] [d] pyrans and pyranonesrepresented by the formula ##STR2## wherein R₁ is methyl or R₁ R₁ isoxygen; R₂ is alkyl or halogen substituted phenyl alkyl; and R₃ ishydrogen, loweralkyl, loweralkenyl or loweralkynyl.

As used herein the term "loweralkyl" refers to C₁ -C₆ straight orbranched chain alkylene groups including methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl, n-hexyl and the like.

The term "alkyl" refers to straight and branched chain alkyl radicalshaving from 1 to 20 carbons atoms such as methyl, n-amyl,3-methyl-2-octyl, 2-nonyl,2-eicosanyl and the like.

The term "halogen" includes chlorine, fluorine, bromine and iodine.

The term "loweralkenyl" refers to straight and branched chain C₂ -C₆alkyl radicals from which a hydrogen atom has been removed from each oftwo adjacent carbon atoms to produce ethylenic unsaturation; e.g.,vinyl, allyl, methallyl, 1-pentenyl and the like.

The term "loweralkynyl" refers to C₂ -C₆ alkyl groups as defined above,from which two hydrogen atoms have been removed from each of twoadjacent carbon atoms to produce acetylenic unsaturation; e.g., ethynyl,propargyl, 2-butnynyl, 1-pentynyl and the like groups.

The present compounds are prepared according to the following reactionscheme: ##STR3##

In the reaction illustrated above, the starting material,5-hydroxy-4-methyl-7-alkylcoumarin-3-propionate (I), is obtained byreaction of 5-alkylresorcinol with dialkyl β-acetylglutarate in thepresence of phosphorus oxychloride. The coumarin (I) is then cyclized to1-hydroxy-3-alkyl-6, 9-dioxo-7, 8, 9, 10-tetrahydro-6H-dibenzo [b] [d]pyran (II) with sodium hydride in dimethyl sulfoxide, which, in turn, isreduced with sodium borohydride to 1, 9-dihydroxy-3-alkyl-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran (III). Compound (III) is thenconverted to 1, 9-dihydroxy-6, 6-dimethyl-3-alkyl-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran (IV) with methyl magnesiumbromide.

The compounds of this invention are useful as analgesic agents andtranquilizers. The compounds are effective at dosages generally from 1to 10 mg./kg. of body weight daily. The analgesic activity wasestablished in the standard mouse writhing test [Whittle, Brit. J.Pharmacol., 22,296 (1964)] and confirmed in the hot plate assay [Woolfe,G. and MacDonald, A. D., J. Pharmacol. Exper. Therap., 80,300, (1944)]and the rat tail flick test.

The following examples further describe and illustrate the presentinvention.

EXAMPLE 1 Ethyl5-Hydroxy-4-Methyl-7-(3-Methyl-2-Octyl)Coumarin-3-Propionate ##STR4##

A mixture of 262 g. (1.109 mole) of 5-(3-methyl-2-octyl)resorcinol, 283g. (1.23 mole) of diethyl α-acetylglutarate, and 170 g. (1.11 mole) ofphorphorus oxychloride protected from atmospheric mositure is stirred atroom temperature for 12 days. The mixture is taken up in benzene-etherand the solution is washed several times with water, aqueous sodiumbicarbonate, water and dried over anhydrous magnesium sulfate. Afterremoval of the solvent, 441 g. of an oil is obtained, which solidifieson standing.

EXAMPLE 2 Ethyl7-[5-(p-Fluorophenyl)-2-Pentyl]-5-Hydroxy-4-Methylcoumarin-3-Propionate##STR5##

Ethyl7-[5-(p-fluorophenyl)-2-pentyl]-5-hydroxy-4-methylcoumarin-3-propionateis prepared by reaction of 5-[5-(p-fluorophenyl)-2-pentyl]resorcinol,diethyl α-acetylglutarate, and phosphorus oxychloride according to themethod of Example 1.

EXAMPLE 3 1-Hydroxy-3-(3-Methyl-2-Octyl)-6, 9-Dioxo-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR6##

To a stirred solution of 43.8 g. (0.1088 mole) of ethyl5-hydroxy-4-methyl-7-(3-methyl-2-octyl)coumarin-3-propionate in 325 ml.of dry reagent grade dimethyl sulfoxide is added, portionwise, 19.6 g.(0.466 mole) of 57% sodium hydride in mineral oil. The mixture isstirred at room temperature overnight and poured into 1200 ml. of iceand water. The dark solution is extracted twice with ether to remove themineral oil. Concentrated hydrochloric acid (75 ml.) is added to thestirred aqueous solution and after 1 hour of stirring, the slurry isfiltered and the solid is washed well with water. The wet filter cake isheated on the steam bath with excess concentrated sodium bicarbonatesolution and is filtered. The solid is washed well with water andrecrystallized from acetonitrile to give the pure product; m.p.150-151°.

Analysis Calcd. for C₂₂ H₂₈ O₄ : C, 74.13; H, 7.92; O, 17.95; Found: C,73.70; H, 7.98; O, 18.34

EXAMPLE 4 3-[5-(p-Fluorophenyl)-2-Pentyl]-1-Hydroxy-6, 9-Dioxo-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR7##

3-[5-(p-Fluorophenyl)-2-pentyl]-1-hydroxy-6, 9-dioxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting ethyl7-[5-(p-fluorophenyl)-2-pentyl]-5-hydroxy-4-methylcoumarin-3-propionatewith sodium hydride in dimethyl sulfoxide according to the method ofExample 3; m.p. 174°-176°.

EXAMPLE 5 1, 9-Dihydroxy-3-(3-Methyl-2-Octyl)-6-Oxo-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR8##

A mixture of 3.56 g. (0.01 mole) of 1-hydroxy-3-(3-methyl-2-octyl)-6,9-dioxo-7, 8, 9, 10-tetrahydro-6H-dibenzo [b] [d] pyran, 3.8 g. (0.1mole) of sodium borohydride, 80 ml. of tetrahydrofuran, 5 ml. of 5%sodium hydroxide solution and 5 ml. of water is stirred and refluxed for20 hours. With addition of 40 ml. of water, the mixture is refluxed foranother one-half hour. The tetrahydrofuran is evaporated in vacuo, andthe residue is extracted with chloroform. After removal of the solvent,an amorphous solid is obtained; m.p. 88°-90°.

Analysis Calcd. for C₂₂ H₃₀ O₄ : C, 73.71; H, 8.44; O, 17.85; Found: C,73.49; H, 8.60; O, 17.97

EXAMPLE 6 3-[5-(p-Fluorophenyl)-2-Pentyl]-1, 9-Dihydroxy-6-Oxo-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR9##

A mixture of 11.3 g. (0.0286 mole) of3-[5-(p-fluorophenyl-2-pentyl]-1-hydroxy-6, 9-dioxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran, 10.9 g. (0.286 mole) of sodiumborohydride, 200 ml. of tetrahydrofuran, 10 ml. of 5% sodium hydridesolution and 10 ml. of water is stirred and refluxed for 19 hours. Withaddition of 60 ml. of water, the mixture is refluxed for anotherone-half hour. The tetrahydrofuran is evaporated in vacuo, and theresidue is treated with water, acidified with dilute hydrochloric acid,and extracted with chloroform. The chloroform solution is dried overmagnesium sulfate, and evaporated in vacuo. The residue is purified bychromatography on a Florisil® column, using methanol/chloroform solventmixtures to give the pure product; m.p. 87°-92°.

Analysis Calcd. for C₂₄ H₂₅ FO₄ : C, 72.71; H, 6.36; Found: C, 72.98; H,6.36

EXAMPLE 7 1, 9-Dihydroxy-6, 6-Dimethyl-3-(3-Methyl-2-Octyl)-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR10##

A solution of 3.4 g. (0.00948 mole) of1,9-dihydroxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran in 75 ml. of ether is addeddropwise to a stirred solution of 31.6 ml. (0.0948 mole) of methylmagnesium bromide 3/M in ether. The mixture is stirred and refluxed for20 hours. The complex is decomposed by addition of water, followed byammonium chloride solution. The ether solution is decanted and thegelatinous inorganic salt is washed well with ether. The combined ethersolution is dried and evaporated in vacuo. The residue is dissolved inbenzene and refluxed with a few crystals of p-toluenesulfonic acidmonohydrate for one-half hour, with a Dean-Stark trap to remove thewater formed. After removal of the solvent, the residue ischromatographed on a Florisil® (60-100/mesh) column, using gradedmethanol/chloroform solvent mixtures to yield the pure product.

Analysis Calcd. for C₂₄ H₃₆ O₃ : C, 77.37; H, 9.74; O, 12.89; Found: C,77.47; H, 9.80; O, 13.44

EXAMPLE 8 3-[5-(p-Fluorophenyl)-2-Pentyl]-1, 9-Dihydroxy-6,6-Dimethyl-7, 8, 9, 10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR11##

3-[5-(p-Fluorophenyl)-2-pentyl]-1, 9-dihydroxy-6, 6-dimethyl-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting3-[5-(p-fluorophenyl)-2-pentyl]-1, 9-dihydroxy-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo-[b] [d] pyran with methyl magnesium bromideaccording to the method of Example 7. The crude product is purified bychromatography on a Florisil® column, using chloroform as eluant.

Analysis Calcd. for C₂₆ H₃₁ FO₃ : C, 76.07; H, 7.61; Found: C, 75.57; H,7.59

EXAMPLE 9 9-Hydroxy-1-Methoxy-3-(3-Methyl-2-Octyl)-6-Oxo-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR12##

A solution of 8.0 g. (0.0224 mole) of 1-hydroxy-3-(3-methyl-2-octyl)-6,9-dioxo-7, 8, 9, 10tetrahydro-6H-dibenzo [b] [d] pyran in 50 ml. ofdimethyl formamide is added dropwise to a stirred suspension of 1.7 g.(0.04 mole) of sodium hydride (57% in mineral oil). The mixture isstirred and heated in an oil bath at 80° for 2 hours. After cooling,0.83 g. (0.005 mole) of potassium iodide is added, followed by dropwiseaddition of 5.9 g. (0.042 mole) of methyl iodide. The mixture is stirredat room temperature for 48 hours. After addition of 100 ml. of water,the mixture is extracted with ether. The ether extract is washed withwater, dried, and evaporated in vacuo. The residue is reduced withsodium borohydride according to Example 5. The crude produce is purifiedby chromatography on a Florisil® column, using gradedmethanol/chloroform solvent mixtures.

EXAMPLE 10 9-Hydroxy- 1-Methoxy-6, 6-Dimethyl-3-(3-Methyl-2-Octyl)-7, 8,9, 10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR13##

9-Hydroxy-1-methoxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting9-hydroxy-1-methoxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran with methyl magnesium bromideaccording to the method of Example 7. The crude product is purified bychromatography on a Florisil® column, using chloroform as eluant.

Analysis Calcd. for C₂₅ H₃₈ O₃ : C, 77.67; H, 9.91; O, 12.42; Found: C,77.43; H, 10.05; O, 12.21

EXAMPLE 11 1-Allyloxy-9-Hydroxy-3-(3-Methyl-2-Octyl)-6-Oxo-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR14##

1-Allyloxy-9-hydroxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting1-hydroxy-3-(3-methyl-2-octyl)-6, 9-dioxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran with allyl bromide and reducingthe product with sodium borohydride according to the method of Example9.

EXAMPLE 12 9-Hydroxy-3-(3-Methyl-2-Octyl)-1-(2-Propynyloxy)-6-Oxo-7, 8,9, 10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR15##

9-Hydroxy-3-(3-methyl-2-octyl)-1-(2-propynyloxy)-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting1-hydroxy-3-(3-methyl-2-octyl)-6, 9-dioxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran with 2-propynyl bromide andreducing the product with sodium borohydride according to the method ofExample 9.

EXAMPLE 13 1-Allyloxy-9-Hydroxy-6, 6-Dimethyl-3-(3-Methyl-2-Octyl)-7, 8,9, 10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR16##

1-Allyloxy-9-hydroxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting1-allyloxy-9-hydroxy-3-(3-methyl-2-octyl)-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran with methyl magnesium bromideaccording to the method of Example 10.

EXAMPLE 14 9-Hydroxy-6,6-Dimethyl-3-(3-Methyl-2-Octyl)-1-(2-Propynyloxy)-7, 8, 9,10-Tetrahydro-6H-Dibenzo [b] [d] Pyran ##STR17##

9-Hydroxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-1-(2-propynyloxy)-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran is prepared by reacting9-hydroxy-3-(3-methyl-2-octyl)-1-(2-propynyloxy)-6-oxo-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran with methyl magnesium bromideaccording to the method of Example 10.

The present invention includes within its scope, pharmaceuticalcompositions comprising, as an active ingredient, at least one of thecompounds of this invention in association with a pharmaceuticallyacceptable carrier or diluent. The compounds of this invention exhibitboth oral and parenteral activity and can be formulated in dosage formsfor oral, parenteral or rectal administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert diluent such as sucrose,lactose or starch. Such dosage forms can also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate, and sweetening andflavoring agents. Tablets and pills can additionally be prepared withenteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water.Besides inert diluents, such compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil, andinjectable organic esters such as ester oleate. Such dosage forms mayalso contain adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, by incorporating sterilizing agentsinto the compositions, by irradiating the compositions, or by heatingthe compositions. They can also be manufactured in the form of sterilesolid compositions which can be dissolved in sterile water, or someother sterile injectable medium immediately before use.

Compositions for rectal administration are suppositories which maycontain in addition to the active substance, excipients such as cocoabutter or a suppository wax.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient shall be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration and on the duration of the treatment.

We claim:
 1. A compound of the formula ##STR18## wherein R₁ is methyl,R₂ is C₁ -C₂₀ alkyl and R₃ is hydrogen, loweralkyl, C₂ -C₆ alkenyl or C₂-C₆ alkynyl.
 2. A compound in accordance with claim 1, wherein each R₁is methyl, R₂ is C₁ -C₂₀ alkyl, and R₃ is hydrogen.
 3. A compound inaccordance with claim 2, 1, 9-dihydroxy-6,6-dimethyl-3-(3-methyl-2-octyl)-7, 8, 9, 10-tetrahydro-6H-dibenzo [b][d] pyran.
 4. A compound in accordance with claim 1, wherein each R₁ ismethyl, R₂ is alkyl, and R₃ is CH₃.
 5. A compound in accordance withclaim 4, 9-hydroxy-1-methoxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran.
 6. A compound in accordance withclaim 1, wherein each R₁ is methyl, R₂ is alkyl, and R₃ is C₂ -C₆alkenyl.
 7. A compound in accordance with claim 6,1-allyloxy-9-hydroxy-6, 6-dimethyl-3-(3-methyl-2-octyl)-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran.
 8. A compound in accordance withclaim 1, wherein each R₁ is methyl, R₂ is alkyl, and R₃ is C₂ -C₆alkynyl.
 9. A compound in accordance with claim 8, 9-hydroxy-6,6-dimethyl-3-(3-methyl-2-octyl)-1-(2-propynyloxy)-7, 8, 9,10-tetrahydro-6H-dibenzo [b] [d] pyran.